Por favor, use este identificador para citar o enlazar este Item:http://hdl.handle.net/20.500.12105/5246
Título
CLOCK gene variation is associated with incidence of type-2 diabetes and cardiovascular diseases in type-2 diabetic subjects: dietary modulation in the PREDIMED randomized trial
Autor(es)
Corella, Dolores | Asensio, Eva M. | Coltell, Oscar | Sorli, Jose V. | Estruch, Ramon | Angel Martinez-Gonzalez, Miguel | Salas-Salvado, Jordi | Castaner, Olga | Aros, Fernando | Lapetra, Jose | Serra-Majem, Lluis | Gomez-Gracia, Enrique | Ortega-Azorin, Carolina | Fiol, Miquel | Diez Espino, Javier | Diaz-Lopez, Andres | Fito, Montserrat | Ros, Emilio | Ordovas, Jose M CNIC
Fecha de publicación
2016
Cita
Cardiovasc Diabetol. 2016; 15(1):4
Idioma
Inglés
Tipo de documento
research article
Resumen
Background: Circadian rhythms regulate key biological processes influencing metabolic pathways. Disregulation is associated with type 2 diabetes (T2D) and cardiovascular diseases (CVD). Circadian rhythms are generated by a transcriptional autoregulatory feedback loop involving core clock genes. CLOCK (circadian locomotor output cycles protein kaput), one of those core genes, is known to regulate glucose metabolism in rodent models. Cross-sectional studies in humans have reported associations between this locus and obesity, plasma glucose, hypertension and T2D prevalence, supporting its role in cardiovascular risk. However, no longitudinal study has investigated the association between CLOCK gene variation and T2D or CVD incidence. Moreover, although in a previous work we detected a gene-diet interaction between the CLOCK-rs4580704 (C > G) single nucleotide polymorphism (SNP) and monounsaturated (MUFA) intake on insulin resistance, no interventional study has analyzed gene-diet interactions on T2D or CVD outcomes. Methods: We analyzed the association between the CLOCK-rs4580704 SNP and incidence of T2D and CVD longitudinally in 7098 PREDIMED trial (ISRCTN35739639) participants after a median 4.8-year follow-up. We also examined modulation by Mediterranean diet (MedDiet) intervention (high in MUFA) on these associations. Results: We observed a significant association between the CLOCK-rs4580704 SNP and T2D incidence in n = 3671 non-T2D PREDIMED participants, with variant allele (G) carriers showing decreased incidence (dominant model) compared with CC homozygotes (HR: 0.69; 95 \% CI 0.54-0.87; P = 0.002). This protection was more significant in the MedDiet intervention group (HR: 0.58; 95 \% CI 0.43-0.78; P < 0.001) than in the control group (HR: 0.95; 95 \% CI 0.63-1.44; P = 0.818). Moreover, we detected a statistically significant interaction (P = 0.018) between CLOCK-rs4580704 SNP and T2D status on stroke. Thus, only in T2D subjects was CLOCK-rs4580704 SNP associated with stroke risk, G-carriers having decreased risk (HR: 0.61; 95 \% CI 0.40-0.94; P = 0.024 versus CC) in the multivariable-adjusted model. Conclusions: In agreement with our previous results showing a protective effect of the G-allele against hyperglycemia, we extended our findings by reporting a novel association with lower T2D incidence and also suggesting a dietary modulation. Moreover, we report for the first time an association between a CLOCK polymorphism and stroke in T2D subjects, suggesting that core clock genes may significantly contribute to increased CVD risk in T2D.
Palabras clave
CLOCK gene | Diabetes | Cardiovascular diseases | Stroke | Mediterranean diet | ACUTE MYOCARDIAL-INFARCTION | MAMMALIAN CIRCADIAN CLOCK | BLOOD-PRESSURE SURGE | METABOLIC SYNDROME | TRANSCRIPTION FACTOR | MEDITERRANEAN DIET | DNA METHYLATION | SLEEP DURATION | RISK-FACTORS | OBESITY
MESH
Aged, 80 and over | Aged | CLOCK Proteins | Risk Assessment | Humans | Circadian Rhythm | Protective Factors | Homozygote | Phenotype | Male | Multivariate Analysis | Time Factors | Chi-Square Distribution | Risk Factors | Incidence | Cardiovascular Diseases | Diabetes Mellitus, Type 2 | Genetic Predisposition to Disease | Kaplan-Meier Estimate | Spain | Gene Frequency | Heterozygote | Middle Aged | Polymorphism, Single Nucleotide | Longitudinal Studies | Proportional Hazards Models | Treatment Outcome | Diet, Mediterranean | Gene-Environment Interaction
DECS
Dieta Mediterránea | Modelos de Riesgos Proporcionales | Resultado del Tratamiento | Masculino | Factores Protectores | Interacción Gen-Ambiente | Estudios Longitudinales | Persona de Mediana Edad | Frecuencia de los Genes | Heterocigoto | Estimación de Kaplan-Meier | Medición de Riesgo | Diabetes Mellitus Tipo 2 | Enfermedades Cardiovasculares | Incidencia | Polimorfismo de Nucleótido Simple | Distribución de Chi-Cuadrado | Predisposición Genética a la Enfermedad | Factores de Tiempo | Análisis Multivariante | Homocigoto | Factores de Riesgo | Proteínas CLOCK | Humanos | Ritmo Circadiano | Anciano | Fenotipo | Anciano de 80 o más Años | España
Versión en línea
DOI
Aparece en las colecciones
- Investigación > IIS > IdisBa - Instituto de Investigación Sanitaria Illes Balears (Baleares)
- Investigación > IIS > IMIM - Hospital del Mar Research Institute-Barcelona (Cataluña)
- Investigación > IIS > IDIBAPS - Instituto de Investigaciones Biomédicas August Pi i Sunyer (Cataluña)
- Investigación > CNIC > Grupos de investigación
- Investigación > IIS > IdiSNA - Instituto de Investigación Sanitaria de Navarra (Navarra)
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